Field of the Invention
The present invention relates to compounds which inhibit Rho Kinase (hereinafter ROCK Inhibitors). The present invention also relates to methods of preparing such a compound, pharmaceutical compositions which contain such a compound, and therapeutic uses of such a compound.
Discussion of the Background
Rho-associated coiled-coil forming protein kinase (ROCK) belongs to the AGC (PKA/PKG/PKC) family of serine-threonine kinases. Two human isoforms of ROCK have been described, ROCK-I (also referred to as p160 ROCK or ROKβ) and ROCK-II (ROKα) are approximately 160 kDa proteins containing an N-terminal Ser/Thr kinase domain, followed by a coiled-coil structure, a pleckstrin homology domain, and a cysteine-rich region at the C-terminus (see Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446-456, which is incorporated herein by reference in its entirety).
Both ROCK-II and ROCK-I are expressed in many human and rodent tissues including the heart, pancreas, lung, liver, skeletal muscle, kidney and brain (see Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446-456, which is incorporated herein by reference in its entirety). ROCK has been identified as an effector molecule of RhoA, and is involved in a variety of cell functions, including actin organization, cell adhesion, cell migration and cytokinesis (see Riento, K.; Ridley, A. J. Rocks: multifunctional kinases in cell behaviour. Nat. Rev. Mol. Cell Biol. 2003, 4, 446-456; and Feng Y, LoGrasso P V, Defert O, Li R. Rho Kinase (ROCK) Inhibitors and Their Therapeutic Potential. J Med Chem. 2016; 59(6):2269-300, which are incorporated herein by reference in their entireties). It is also involved in regulating smooth muscle contraction, through the phosphorylation of effectors such as myosin light chain phosphatase (MLC). Indeed ROCK plays an important role in signal transduction initiated by several agents regulating smooth muscle cell contraction in blood vessels and/or airways, including serotonin, angiotensin II, endothelin I, platelet derived growth factor (PDGF) and urotensin II (see Li Q, Xu Y, Li X, Guo Y, Liu G. Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: role of TGF-β1-TAK1. Toxicol Lett. 2012; 211(2):91-7; and Shi J, Wei L. Rho kinases in cardiovascular physiology and pathophysiology: the effect of fasudil. J Cardiovasc Pharmacol. 2013; 62(4):341-54, which are incorporated herein by reference in their entireties). To date only two ROCK inhibitors have been approved for clinical use, in Japan and/or in China: Fasudil (see Suzuki Y, Shibuya M, Satoh S, Sugiyama H, Seto M, Takakura K. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo). 2008; 48(6):241-7, which is incorporated herein by reference in its entirety) was approved in 1995 for the treatment of cerebral vasospasm, and ripasudil (see Tanihara H, Inoue T, Yamamoto T, Kuwayama Y, Abe H, Fukushima A, Suganami H, Araie M; K-115 Clinical Study Group. One-year clinical evaluation of 0.4% ripasudil (K-115) in patients with open-angle glaucoma and ocular hypertension. Acta Ophthalmol. 2016; 94(1):e26-34, which is incorporated herein by reference in its entirety) was approved in 2014 for the treatment of glaucoma.
ROCK mediate vasoconstriction and endothelial dysfunction are two key components of several cardiovascular diseases, including, hypertensive heart disease, coronary artery diseases, atherosclerosis, restenosis, Raynaud phenomenon, stroke and glaucoma (see Hartmann S, Ridley A J, Lutz S. The Function of Rho-Associated Kinases ROCK1 and ROCK2 in the Pathogenesis of Cardiovascular Disease. Front Pharmacol. 2015 Nov. 20; 6:276, which is incorporated herein by reference in its entirety). In particular, pharmacological data from clinical trials show that ROCK inhibitors decrease intraocular pressure and demonstrate beneficial effects in glaucoma patients (see Inoue T, Tanihara H. Rho-associated kinase inhibitors: a novel glaucoma therapy. Prog Retin Eye Res. 2013; 37:1-12, which is incorporated herein by reference in its entirety). In patients with pulmonary hypertension, ROCK activity is significantly higher in both lung tissues and circulating neutrophils as compared with controls (see Duong-Quy S, Bei Y, Liu Z, Dinh-Xuan A T. Role of Rho-kinase and its inhibitors in pulmonary hypertension. Pharmacol Ther. 2013; 137(3):352-64, which is incorporated herein by reference in its entirety). A significant correlation was established between neutrophil ROCK activity and the severity and duration of pulmonary hypertension (see Duong-Quy S, Bei Y, Liu Z, Dinh-Xuan A T. Role of Rho-kinase and its inhibitors in pulmonary hypertension. Pharmacol Ther. 2013; 137(3):352-64, which is incorporated herein by reference in its entirety). ROCK can also contribute to the development of cardiac fibrosis, hypertrophy, and subsequent heart failure. Recent experimental studies using ROCK inhibitors, such as fasudil, have shown the benefits of ROCK inhibition in cardiac remodeling (see Li Q, Xu Y, Li X, Guo Y, Liu G. Inhibition of Rho-kinase ameliorates myocardial remodeling and fibrosis in pressure overload and myocardial infarction: role of TGF-β1-TAK1. Toxicol Lett. 2012; 211(2):91-7, which is incorporated herein by reference in its entirety). Mice lacking each ROCK isoform also exhibit reduced myocardial fibrosis in a variety of pathological models of cardiac remodeling (see Shimizu Ti, Liao J K. Rho Kinases and Cardiac Remodeling. Circ J. 2016; 80(7):1491-8, which is incorporated herein by reference in its entirety).
ROCK is also a promising target for the treatment of cerebral vascular disorders. Indeed, preclinical studies indicate that Rho kinase inhibition may reduce the formation/growth/rupture of both intracranial aneurysms and cerebral cavernous malformations (see Bond L M, Sellers J R, McKerracher L. Rho kinase as a target for cerebral vascular disorders. Future Med Chem. 2015; 7(8):1039-53, which is incorporated herein by reference in its entirety).
RhoA-ROCK signalling is important in maintaining a flaccid penile state, and pharmacological inhibition of ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner, suggesting that ROCK is a new therapeutic target for the treatment of erectile dysfunction (see Sopko N A, Hannan J L, Bivalacqua T J. Understanding and targeting the Rho kinase pathway in erectile dysfunction. Nat Rev Urol. 2014; 11(11):622-8, which is incorporated herein by reference in its entirety).
ROCK activity is an important signaling mechanism in leucocyte-platelet-endothelium interaction, leucocyte extravasation and oedema. Overactivation of Rho kinase in endothelial cells causes leakiness by disruption of cell-cell junctions favouring inflammatory cell recruitment. Taken together, this evidence point toward a role of ROCK in pathological conditions associated with acute and chronic inflammation as well as autoimmune diseases. In particular, contribution of the ROCK pathway to autoimmunity and autoimmune disease is emerging (see Zanin-Zhorov A, Flynn R, Waksal S D, Blazar B R. Isoform-specific targeting of ROCK proteins in immune cells. Small GTPases. 2016; 7(3):173-177, which is incorporated herein by reference in its entirety). This is supported by the demonstration of the role of ROCK signaling in T-cell development and function, including adhesion, chemotactic responses, and antigen-dependent activation, as well as the beneficial effect of ROCK inhibition in experimental models of rheumatoid arthritis and lupus (see LoGrasso, P.; Feng, Y. Rho kinase inhibitors and their application to inflammatory disorders. Curr. Top. Med. Chem. 2009; 9, 704-723; Yoshimi, E.; Kumakura, F.; Hatori, C.; Hamachi, E.; Iwashita, A.; Ishii, N.; Terasawa, T.; Shimizu, Y.; Takeshita, N. Antinociceptive effects of AS1892802, a novel rho kinase inhibitor, in rat models of inflammatory and noninflammatory arthritis. J. Pharmacol. Exp. Ther. 2010, 334, 955-963; and Stirzaker R A, Biswas P S, Gupta S, Song L, Bhagat G, Pernis A B. Administration of fasudil, a ROCK inhibitor, attenuates disease in lupus-prone NZB/W F1 female mice. Lupus. 2012 May; 21(6):656-61, which are incorporated herein by reference in their entireties). The inhibitory effect of Fasudil on T-cell migration might expand its clinical application as a new therapy for multiple sclerosis (see Yu J Z, Ding J, Ma C G, Sun C H, Sun Y F, Lu C Z, Xiao B G. Therapeutic potential of experimental autoimmune encephalomyelitis by Fasudil, a Rho kinase inhibitor. J Neurosci Res. 2010; 88(8):1664-72, which is incorporated herein by reference in its entirety). Accumulating evidence also demonstrates that ROCK plays a key role in regulating three essential factors for pathogenesis of inflammatory bowel disease (IBD): disruptions of the intestinal barrier, exposure of the luminal content to mucosal immune cells and an abnormal immune response (see Huang Y, Xiao S, and Jiang Q. Role of Rho kinase signal pathway in inflammatory bowel disease Int J Clin Exp Med. 2015; 8(3): 3089-3097, which is incorporated herein by reference in its entirety). The clinical use of ROCK inhibitors is under scrutiny also in psoriasis (see Yiu Z Z, Warren R B. Novel Oral Therapies for Psoriasis and Psoriatic Arthritis. Am J Clin Dermatol. 2016; 17(3):191-200, which is incorporated herein by reference in its entirety).
There are several lines of evidence that ROCKs play a role in the pathology of diabetes. Indeed, ROCK1 KO mice exhibit insulin resistance and can have a significant increase in glucose-induced insulin secretion, leading to hyperinsulinemia (see Lee D. H., Shi J., Jeoung N. H., Kim M. S., Zabolotny J. M., Lee S. W., et al. Targeted disruption of ROCK1 causes insulin resistance in vivo. J. Biol, Chem. 2009; 284, 11776-11780, which is incorporated herein by reference in its entirety). In addition, studies in models of type 1 and type 2 diabetes have indicated blood pressure-independent nephroprotective actions of ROCKi in diabetic kidney disease (see Komers R. Rho kinase inhibition in diabetic kidney disease. Br J Clin Pharmacol. 2013; 76(4):551-9, which is incorporated herein by reference in its entirety).
There is now substantial evidence that ROCK is involved in many of the pathways that contribute to the pathologies associated with several acute and chronic pulmonary diseases, including asthma, COPD, bronchiectasis and ARDS/ALI. Given the biological effect of ROCK, selective inhibitors have the potential to treat a number of pathological mechanisms in respiratory diseases, such as smooth muscle hyper-reactivity, bronchoconstriction, airway inflammation and airway remodeling, neuromodulation and exacerbations due to respiratory tract viral infection (see Fernandes L B, Henry P J, Goldie R G. Rho kinase as a therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease. Ther Adv Respir Dis. 2007 October; 1(1):25-33, which is incorporated herein by reference in its entirety). Indeed the Rho kinase inhibitor Y-27632 causes bronchodilatation and reduces pulmonary eosinophilia trafficking and airways hyperresponsiveness (see Gosens, R.; Schaafsma, D.; Nelemans, S. A.; Halayko, A. J. Rhokinase as a drug target for the treatment of airway hyperresponsiveness in asthma. Mini-Rev. Med. Chem. 2006, 6, 339-348, which is incorporated herein by reference in its entirety). Pulmonary ROCK activation has been demonstrated in humans with idiopathic pulmonary fibrosis (IPF) and in animal models of this disease. ROCK inhibitors can prevent fibrosis in these models, and more importantly, induce the regression of already established fibrosis, thus indicating ROCK inhibitors as potential powerful pharmacological agents to halt progression of pulmonary fibrosis (see Jiang, C.; Huang, H.; Liu, J.; Wang, Y.; Lu, Z.; Xu, Z. Fasudil, a rho-kinase inhibitor, attenuates bleomycin-induced pulmonary fibrosis in mice. Int. J. Mol. Sci. 2012, 13, 8293-8307, which is incorporated herein by reference in its entirety).
Accumulating evidence supports the concept that ROCK plays important roles in tumor development and progression through regulating many key cellular functions associated with malignancy, including tumorigenicity, tumor growth, metastasis, angiogenesis, tumor cell apoptosis/survival and chemoresistance (see Wei L, Surma M, Shi S, Lambert-Cheatham N, Shi J. Novel Insights into the Roles of Rho Kinase in Cancer. Arch Immunol Ther Exp (Warsz). 2016; 64(4):259-78, which is incorporated herein by reference in its entirety). Thus, indicating ROCK inhibitors also as potential powerful pharmacological agents in cancer.
The administration of an oral ROCK inhibitor effectively ameliorates clinical manifestations in experimental models of graft-vs.-host disease (GVHD) (see Biol Blood Marrow Transplant. 2014; 20(8):1104-11; and Blood. 2016; 127(17):2144-54, which are incorporated herein by reference in their entireties). Further findings highlight the Rho kinases as rational therapeutic targets to combat tau accumulation in Progressive Supranuclear Palsy (PSP) and Corticobasal Degeneration (CBD) (see Gentry et al., J Neurosci. 2016; 36(4):1316-23, which is incorporated herein by reference in its entirety).
In various disorders of the central nervous system there is an abnormal activation of the Rho/ROCK pathway. ROCK is activated upon injury to the adult brain and spinal cord and inhibition of ROCKs results in accelerated regeneration and enhanced functional recovery after spinal-cord injury (see Kubo T, Hata K, Yamaguchi A, Yamashita T. Rho-ROCK inhibitors as emerging strategies to promote nerve regeneration. Curr Pharm Des. 2007; 13(24):2493-9, which is incorporated herein by reference in its entirety). Inhibition of the Rho/ROCK pathway has also proved to be efficacious in animal models of stroke, inflammatory and demyelinating diseases, Alzheimer's disease and neuropathic pain (reviewed by Mueller, B. K.; Mack, H.; Teusch, N. Rho kinase, a promising drug target for neurological disorders. Nat. Rev. Drug Discovery 2005, 4, 387-398, which is incorporated herein by reference in its entirety).
Various compounds have been described in the literature as Rho Kinase Inhibitors. See e.g. WO 2004/039796; WO 2006/009889; WO 2010/032875; WO 2009/079008; and WO 2014/118133, which are incorporated herein by reference in their entireties.
There remains, however, a potential for developing novel and pharmacologically improved ROCK inhibitors in many therapeutic areas such as: cardiovascular and respiratory diseases, erectile dysfunction, fibrotic diseases, insulin resistance, kidney failure, central nervous system disorders, auto-immune diseases and oncology.
In view of the number of pathological responses which are mediated by ROCK enzymes, there is a continuing need for inhibitors of such enzymes which can be useful in the treatment of many disorders.